The ultimate aim of these studies is to develop potent antiestrogens capable of controlling growth of estrogen-dependent tumors in humans by non-invasive endocrine therapy. Because of their known specific interaction with estrogen receptors, antiestrogens seem particularly well suited to be specific, antitumor agents in the cases of estrogen-dependent tumors, theoretically capable of achieving non- surgical endocrine therapy. Initially, we will monitor, in a comparative manner, the effects of a number of structurally related antiestrogens and proestrogens on estrogen-stimulated growth responses in the immature rat uterus and vagina, where the biosynthetic sequence of events following estrogen has been well characterized. In this model system we will attempt to elucidate the cellular (receptor occupancy) and pharmacodynamic factors (uptake, distribution, metabolism, rates of clearance) influencing antiestrogen effectiveness. Utilizing this information, we will then conduct studies to elucidate the probable bases of antiestrogenic inhibition of tumor development and growth in the dimethylbenzanthracene (DMBA)-induced rat mammary tumor system with our most effective antiestrogens. Specific efforts will be directed to determining (1) the effectiveness of short and long-acting estrogens in promoting development and growth of DMBA-induced mammary tumors; (2) the effectiveness of antiestrogens in inhibiting tumor formation and in arresting the growth of established tumors; and (3) the reversibility of antiestrogenic growth interference. Studies will analyze tissue growth parameters and the total estrogen receptor content and distribution in mammary tumor versus uterus of carcinogen-treated animals as a function of time, with simultaneous monitoring of the prolactin level in serum. These studies should elucidate the factors optimizing retardation of the growth of estrogen-dependent tissues and tumors by antiestrogens, and should enable the clinical use of antiestrogens to be approached with greater rationale.